This invention relates to processes for the preparation of pirbuterol and analogs, compounds of the formula ##STR2## wherein R is hydrogen, methyl or hydroxymethyl and the intermediates therefor, including processes for the conversion of compounds of the formula (I) wherein R is hydrogen or methyl into pirbuterol [formula I, wherein R is hydroxymethyl].
Pirbuterol and its bronchodilator activity were originally described by Barth in a series of U.S. Pat. Nos. (3,700,681; 3,763,173; 3,772,314; 3,786,160). At that time, pirbuterol was synthesized as follows: ##STR3##
The pirbuterol analogs of the formula I, wherein R is hydrogen, methyl, or methanesulfonylmethyl, and their bronchodilator activity, were disclosed by Jen and Kaiser in U.S. Pat. No. 3,952,101. These compounds were prepared from the corresponding aldehydes by a reaction sequence fully analogous with that of the earlier pirbuterol process.
Subsequently, an alternative, preferred process for the synthesis of pirbuterol was described by Nakanishi (U.S. Pat. Nos. 3,948,919; 4,031,108), exemplified as follows: ##STR4## Improvements and alternatives to this process have also been described, viz., isolation of the pirbuterol precursor as a maleate salt (Carroll et al., U.S. Pat. No. 4,011,231) and hydrogenolysis rather than hydrolysis as the final stage (Argentina Pat. No. 214005, Luxembourg Pat. No. 79564).
The latter process still suffers from the disadvanatge of generating noxious sulfide by-products in the preparation of epoxide. Even under the best of conditions, traces of sulfur can carry through and increase the catalyst level when protecting groups are removed by hydrogenolysis, the preferred route when the free base form of pirbuterol is desired. Furthermore, the epoxide is relatively unreactive towards the tertbutylamine reagent, even under pressure at elevated temperatures requiring large excess of the reagent and a relatively long time to achieve complete reaction.
A further disadvantage of the improved process is the polar nature of intermediate amino alcohol, making this intermediate difficult to isolate in pure form.
Recently pirbuterol has been discovered to also have utility for the treatment of congestive heart failure (Taylor, U.S. Pat. No. 4,175,128).
In a chemical transformation related to one of the process steps of the present invention, Benderly et al., [Can. J. Chem. 56, pp. 2673-2676 (1978)] have reported the conversion of 2-vinylpyridine to 2-(1,2-epoxyethyl)-pyridine N-oxide by the action of m-chloroperbenzoic acid on 2-vinylpyridine.